Insight into the mechanism of the initial reaction of a OH-radical with DNA/RNA nucleobases: a computational investigation of radiation damage

Birgitte Olai Milhøj; Stephan P. A. Sauer

doi:10.1002/chem.201503107

Insight into the mechanism of the initial reaction of a OH-radical with DNA/RNA nucleobases: a computational investigation of radiation damage

Birgitte Olai Milhøj, Stephan P. A. Sauer

Department of Chemistry

11 Citations (Scopus)

Abstract

Earlier theoretical investigations of the mechanism of radiation damage to DNA/RNA nucleobases have claimed OH radical addition as the dominating pathway based solely on energetics. In this study we supplement calculations of energies with the kinetics of all possible reactions with the OH radical through hydrogen abstraction and OH radical addition onto carbon sites, using DFT at the ωB97X-D/6-311++G(2df,2pd) level with the Eckart tunneling correction. The overall rate constants for the reaction with adenine, guanine, thymine, and uracil are found to be 2.17×10⁻¹², 5.64×10⁻¹¹, 2.01×10⁻¹¹, and 5.03×10⁻¹² cm³ molecules⁻¹ s⁻¹, respectively, which agree exceptionally well with experimental values. We conclude that abstraction of the amine group hydrogen atoms competes with addition onto C₈ as the most important reaction pathway for the purine nucleobases, while for the pyrimidine nucleobases addition onto C₅ and C₆ competes with the abstraction of H₁. Thymine shows favourability against abstraction of methyl hydrogens as the dominating pathway based on rate constants. These mechanistic conclusions are partly explained by an analysis of the electrostatic potential together with HOMO and LUMO orbitals of the nucleobases.

Original language	English
Journal	Chemistry: A European Journal
Volume	21
Issue number	49
Pages (from-to)	17786–17799
Number of pages	14
ISSN	1521-3765
DOIs	https://doi.org/10.1002/chem.201503107
Publication status	Published - 1 Dec 2015

Keywords

Faculty of Science
Radiation Damage
DNA
Adenine
OH radical
Kinetics
DFT calculations
Thermodynamics
Quantum Chemistry
Computational Chemistry
Thymine
Uracil
Guanine
Cytosine

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10.1002/chem.201503107

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title = "Insight into the mechanism of the initial reaction of a OH-radical with DNA/RNA nucleobases: a computational investigation of radiation damage",

abstract = "Earlier theoretical investigations of the mechanism of radiation damage to DNA/RNA nucleobases have claimed OH radical addition as the dominating pathway based solely on energetics. In this study we supplement calculations of energies with the kinetics of all possible reactions with the OH radical through hydrogen abstraction and OH radical addition onto carbon sites, using DFT at the ωB97X-D/6-311++G(2df,2pd) level with the Eckart tunneling correction. The overall rate constants for the reaction with adenine, guanine, thymine, and uracil are found to be 2.17×10−12, 5.64×10−11, 2.01×10−11, and 5.03×10−12 cm3 molecules−1 s−1, respectively, which agree exceptionally well with experimental values. We conclude that abstraction of the amine group hydrogen atoms competes with addition onto C8 as the most important reaction pathway for the purine nucleobases, while for the pyrimidine nucleobases addition onto C5 and C6 competes with the abstraction of H1. Thymine shows favourability against abstraction of methyl hydrogens as the dominating pathway based on rate constants. These mechanistic conclusions are partly explained by an analysis of the electrostatic potential together with HOMO and LUMO orbitals of the nucleobases.",

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AU - Sauer, Stephan P. A.

PY - 2015/12/1

Y1 - 2015/12/1

N2 - Earlier theoretical investigations of the mechanism of radiation damage to DNA/RNA nucleobases have claimed OH radical addition as the dominating pathway based solely on energetics. In this study we supplement calculations of energies with the kinetics of all possible reactions with the OH radical through hydrogen abstraction and OH radical addition onto carbon sites, using DFT at the ωB97X-D/6-311++G(2df,2pd) level with the Eckart tunneling correction. The overall rate constants for the reaction with adenine, guanine, thymine, and uracil are found to be 2.17×10−12, 5.64×10−11, 2.01×10−11, and 5.03×10−12 cm3 molecules−1 s−1, respectively, which agree exceptionally well with experimental values. We conclude that abstraction of the amine group hydrogen atoms competes with addition onto C8 as the most important reaction pathway for the purine nucleobases, while for the pyrimidine nucleobases addition onto C5 and C6 competes with the abstraction of H1. Thymine shows favourability against abstraction of methyl hydrogens as the dominating pathway based on rate constants. These mechanistic conclusions are partly explained by an analysis of the electrostatic potential together with HOMO and LUMO orbitals of the nucleobases.

AB - Earlier theoretical investigations of the mechanism of radiation damage to DNA/RNA nucleobases have claimed OH radical addition as the dominating pathway based solely on energetics. In this study we supplement calculations of energies with the kinetics of all possible reactions with the OH radical through hydrogen abstraction and OH radical addition onto carbon sites, using DFT at the ωB97X-D/6-311++G(2df,2pd) level with the Eckart tunneling correction. The overall rate constants for the reaction with adenine, guanine, thymine, and uracil are found to be 2.17×10−12, 5.64×10−11, 2.01×10−11, and 5.03×10−12 cm3 molecules−1 s−1, respectively, which agree exceptionally well with experimental values. We conclude that abstraction of the amine group hydrogen atoms competes with addition onto C8 as the most important reaction pathway for the purine nucleobases, while for the pyrimidine nucleobases addition onto C5 and C6 competes with the abstraction of H1. Thymine shows favourability against abstraction of methyl hydrogens as the dominating pathway based on rate constants. These mechanistic conclusions are partly explained by an analysis of the electrostatic potential together with HOMO and LUMO orbitals of the nucleobases.

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KW - OH radical

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KW - DFT calculations

KW - Thermodynamics

KW - Quantum Chemistry

KW - Computational Chemistry

KW - Thymine

KW - Uracil

KW - Guanine

KW - Cytosine

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JO - Chemistry: A European Journal

JF - Chemistry: A European Journal

IS - 49

ER -

Insight into the mechanism of the initial reaction of a OH-radical with DNA/RNA nucleobases: a computational investigation of radiation damage

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